Autism-related dietary preferences mediate autism-gut microbiome associations.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

Genetic and environmental influences on fruit and vegetable consumption and depression in older adults.

BACKGROUND: Prior work suggests that higher fruit and vegetable consumption may protect against depression in older adults. Better understanding of the influence of genetic and environmental factors on fruit and vegetable intakes may lead to the design of more effective dietary strategies to increase intakes. In turn this may reduce the occurrence of depression in older adults. OBJECTIVES: The primary aim of this study is to estimate the genetic and environmental influences on the consumption of fruit and vegetables in older adults. The secondary aim is an exploratory analysis into possible shared genetic influences on fruit and vegetable intakes and depression. METHODS: Analysis of observational data from 374 twins (67.1% female; 208 monozygotic (MZ); 166 dizygotic (DZ)) aged ≥ 65 years drawn from the Older Australian Twins Study. Dietary data were obtained using a validated food frequency questionnaire and depressive symptoms were measured using the 15-item short form Geriatric Depression Scale. The contribution of genetic and environmental influences on fruit and vegetable intake were estimated by comparing MZ and DZ twin intakes using structural equation modelling. A tri-variate twin model was used to estimate the genetic and environmental correlation between total fruit and vegetable intakes and depression. RESULTS: In this study, vegetable intake was moderately influenced by genetics (0.39 95%CI 0.22, 0.54). Heritability was highest for brassica vegetables (0.40 95%CI 0.24, 0.54). Overall fruit intake was not significantly heritable. No significant genetic correlations were detected between fruit and vegetable intake and depressive symptoms. CONCLUSIONS: Vegetable consumption, particularly bitter tasting brassica vegetables, was significantly influenced by genetics, although environmental influences were also apparent. Consumption of fruit was only influenced by the environment, with no genetic influence detected, suggesting strategies targeting the food environment may be particularly effective for encouraging fruit consumption.

SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility.

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal-Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn's test P = 0.003), and to heterozygotes (Dunn's test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen's D = - 0.28, P = 0.02), and to heterozygotes (Cohen's D = - 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome.

Persistence of Anxiety/Depression Symptoms in Early Adolescence: A Prospective Study of Daily Life Stress, Rumination, and Daytime Sleepiness in a Genetically Informative Cohort.

In this prospective study of mental health, we examine the influence of three interrelated traits - perceived stress, rumination, and daytime sleepiness - and their association with symptoms of anxiety and depression in early adolescence. Given the known associations between these traits, an important objective is to determine the extent to which they may independently predict anxiety/depression symptoms. Twin pairs from the Queensland Twin Adolescent Brain (QTAB) project were assessed on two occasions (N = 211 pairs aged 9-14 years at baseline and 152 pairs aged 10-16 years at follow-up). Linear regression models and quantitative genetic modeling were used to analyze the data. Prospectively, perceived stress, rumination, and daytime sleepiness accounted for 8-11% of the variation in later anxiety/depression; familial influences contributed strongly to these associations. However, only perceived stress significantly predicted change in anxiety/depression, accounting for 3% of variance at follow-up after adjusting for anxiety/depression at baseline, although it did not do so independently of rumination and daytime sleepiness. Bidirectional effects were found between all traits over time. These findings suggest an underlying architecture that is shared, to some degree, by all traits, while the literature points to hypothalamic-pituitary-adrenal (HPA) axis and/or circadian systems as potential sources of overlapping influence and possible avenues for intervention.

Genetic Specificity of Hippocampal Subfield Volumes, Relative to Hippocampal Formation, Identified in 2148 Young Adult Twins and Siblings.

The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%-72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%-77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%-16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).

ErbB Signaling Pathway Genes Are Differentially Expressed in Monozygotic Twins Discordant for Sports-Related Concussion.

Transcriptional changes involved in neuronal recovery after sports-related concussion (SRC) may be obscured by inter-individual variation in mRNA expression and nonspecific changes related to physical exertion. Using a co-twin study, the objective of this study was to identify important differences in mRNA expression among a single pair of monozygotic (MZ) twins discordant for concussion. A pair of MZ twins were enrolled as part of a larger study of concussion biomarkers among collegiate athletes. During the study, Twin A sustained SRC, allowing comparison of mRNA expression to the nonconcussed Twin B. Twin A clinically recovered by Day 7. mRNA expression was measured pre-injury and at 6 h and 7 days postinjury using Affymetrix HG-U133 Plus 2.0 microarray. Changes in mRNA expression from pre-injury to each postinjury time point were compared between the twins; differences >1.5-fold were considered important. Kyoto Encyclopedia of Genes and Genomes identified biologic networks associated with important transcripts. Among 38,000 analyzed genes, important changes were identified in 153 genes. The ErbB (epidermal growth factor receptor) signaling pathway was identified as the top transcriptional network from pre-injury to 7 days postinjury. Genes in this pathway with important transcriptional changes included epidermal growth factor (2.41), epiregulin (1.73), neuregulin 1 (1.54) and mechanistic target of rapamycin (1.51). In conclusion, the ErbB signaling pathway was identified as a potential regulator of clinical recovery in a MZ twin pair discordant for SRC. A co-twin study design may be a useful method for identifying important gene pathways associated with concussion recovery.

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

OBJECTIVE: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. RESULTS: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. CONCLUSIONS: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

Are Sex Differences in Human Brain Structure Associated With Sex Differences in Behavior?

On average, men and women differ in brain structure and behavior, raising the possibility of a link between sex differences in brain and behavior. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study (n = 1,040) and Human Connectome Project (n = 1,113), we obtained data-driven measures of individual differences along a male-female dimension for brain and behavior based on average sex differences in brain structure and behavior, respectively. We found a weak association between these brain and behavioral differences, driven by brain size. These brain and behavioral differences were moderately heritable. Our findings suggest that behavioral sex differences are, to some extent, related to sex differences in brain structure but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

Region-specific sex differences in the hippocampus.

The hippocampus is a brain region critical for learning and memory, and is also implicated in several neuropsychiatric disorders that show sex differences in prevalence, symptom expression, and mean age of onset. On average, males have larger hippocampal volumes than females, but findings are inconclusive after adjusting for overall brain size. Although the hippocampus is a heterogenous structure, few studies have focused on sex differences in the hippocampal subfields - with little consensus on whether there are regionally specific sex differences in the hippocampus after adjusting for brain size, or whether it is important to adjust for total hippocampal volume (HPV). Here, using two young adult cohorts from the Queensland Twin IMaging study (QTIM; N â€‹= â€‹727) and the Human Connectome Project (HCP; N â€‹= â€‹960), we examined differences between males and females in the volumes of 12 hippocampal subfields, extracted using FreeSurfer 6.0. After adjusting the subfield volumes for either HPV or brain size (brain segmentation volume (BSV)) using four controlling methods (allometric, covariate, residual and matching), we estimated the percentage difference of the sex effect (males versus females) and Cohen's d using hierarchical general linear models. Males had larger volumes compared to females in the parasubiculum (up to 6.04%; Cohen's d â€‹= â€‹0.46) and fimbria (up to 8.75%; d â€‹= â€‹0.54) after adjusting for HPV. These sex differences were robust across the two cohorts and multiple controlling methods, though within cohort effect sizes were larger for the matched approach, due to the smaller sub-sample. Additional sex effects were identified in the HCP cohort and combined (QTIM and HCP) sample (hippocampal fissure (up to 6.79%), presubiculum (up to 3.08%), and hippocampal tail (up to -0.23%)). In contrast, no sex differences were detected for the volume of the cornu ammonis (CA)2/3, CA4, Hippocampus-Amygdala Transition Area (HATA), or the granule cell layer of the dentate gyrus (GCDG). These findings show that, independent of differences in HPV, there are regionally specific sex differences in the hippocampus, which may be most prominent in the fimbria and parasubiculum. Further, given sex differences were less consistent across cohorts after controlling for BSV, adjusting for HPV rather than BSV may benefit future studies. This work may help in disentangling sex effects, and provide a better understanding of the implications of sex differences for behaviour and neuropsychiatric disorders.

Educational attainment polygenic scores are associated with cortical total surface area and regions important for language and memory.

It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N â€‹= â€‹1097) and the USA (N â€‹= â€‹723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R2 â€‹= â€‹0.006 and 0.016 respectively, p â€‹< â€‹0.001) but not average thickness. At the regional level, we identified seven cortical regions-in the frontal and temporal lobes-that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.

Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (ß = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

A unified framework for association and prediction from vertex-wise grey-matter structure.

The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.

Genetic Complexity of Cortical Structure: Differences in Genetic and Environmental Factors Influencing Cortical Surface Area and Thickness.

Quantifying the genetic architecture of the cerebral cortex is necessary for understanding disease and changes to the brain across the lifespan. Prior work shows that both surface area (SA) and cortical thickness (CT) are heritable. However, we do not yet understand the extent to which region-specific genetic factors (i.e., independent of global effects) play a dominant role in the regional patterning or inter-regional associations across the cortex. Using a population sample of young adult twins (N = 923), we show that the heritability of SA and CT varies widely across regions, generally independent of measurement error. When global effects are controlled for, we detected a complex pattern of genetically mediated clusters of inter-regional associations, which varied between hemispheres. There were generally weak associations between the SA of different regions, except within the occipital lobe, whereas CT was positively correlated within lobar divisions and negatively correlated across lobes, mostly due to genetic covariation. These findings were replicated in an independent sample of twins and siblings (N = 698) from the Human Connectome Project. The different genetic contributions to SA and CT across regions reveal the value of quantifying sources of covariation to appreciate the genetic complexity of cortical structures.

16Up: Outline of a Study Investigating Wellbeing and Information and Communication Technology Use in Adolescent Twins.

The '16Up' study conducted at the QIMR Berghofer Medical Research Institute from January 2014 to December 2018 aimed to examine the physical and mental health of young Australian twins aged 16-18 years (N = 876; 371 twin pairs and 18 triplet sets). Measurements included online questionnaires covering physical and mental health as well as information and communication technology (ICT) use, actigraphy, sleep diaries and hair samples to determine cortisol concentrations. Study participants generally rated themselves as being in good physical (79%) and mental (73%) health and reported lower rates of psychological distress and exposure to alcohol, tobacco products or other substances than previously reported for this age group in the Australian population. Daily or near-daily online activity was almost universal among study participants, with no differences noted between males and females in terms of frequency or duration of internet access. Patterns of ICT use in this sample indicated that the respondents were more likely to use online information sources for researching physical health issues than for mental health or substance use issues, and that they generally reported partial levels of satisfaction with the mental health information they found online. This suggests that internet-based mental health resources can be readily accessed by adolescent Australians, and their computer literacy augurs well for future access to online health resources. In combination with other data collected as part of the ongoing Brisbane Longitudinal Twin Study, the 16Up project provides a valuable resource for the longitudinal investigation of genetic and environmental contributions to phenotypic variation in a variety of human traits.

Non-linear realignment improves hippocampus subfield segmentation reliability.

Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.

Accelerated estimation and permutation inference for ACE modeling.

There are a wealth of tools for fitting linear models at each location in the brain in neuroimaging analysis, and a wealth of genetic tools for estimating heritability for a small number of phenotypes. But there remains a need for computationally efficient neuroimaging genetic tools that can conduct analyses at the brain-wide scale. Here we present a simple method for heritability estimation on twins that replaces a variance component model-which requires iterative optimisation-with a (noniterative) linear regression model, by transforming data to squared twin-pair differences. We demonstrate that the method has comparable bias, mean squared error, false positive risk, and power to best practice maximum-likelihood-based methods, while requiring a small fraction of the computation time. Combined with permutation, we call this approach "Accelerated Permutation Inference for the ACE Model (APACE)" where ACE refers to the additive genetic (A) effects, and common (C), and unique (E) environmental influences on the trait. We show how the use of spatial statistics like cluster size can dramatically improve power, and illustrate the method on a heritability analysis of an fMRI working memory dataset.

A Fast Method for Estimating Statistical Power of Multivariate GWAS in Real Case Scenarios: Examples from the Field of Imaging Genetics.

In GWAS of imaging phenotypes (e.g., by the ENIGMA and CHARGE consortia), the growing number of phenotypes considered presents a statistical challenge that other fields are not experiencing (e.g. psychiatry and the Psychiatric Genetics Consortium). However, the multivariate nature of MRI measurements may also be an advantage as many of the MRI phenotypes are correlated and multivariate methods could be considered. Here, we compared the statistical power of a multivariate GWAS versus the current univariate approach, which consists of multiple univariate analyses. To do so, we used results from twin models to estimate pertinent vectors of SNP effect sizes on brain imaging phenotypes, as well as the residual correlation matrices, necessary to estimate analytically the statistical power. We showed that for subcortical structure volumes and hippocampal subfields, a multivariate GWAS yields similar statistical power to the current univariate approach. Our analytical approach is as accurate but ~ 1000 times faster than simulations and we have released the code to facilitate the investigation of other scenarios, may they be outside the field of imaging genetics.

Social Competence in Parents Increases Children's Educational Attainment: Replicable Genetically-Mediated Effects of Parenting Revealed by Non-Transmitted DNA.

We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent's non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children's attainment with their own PRS increased substantially with the standardized effect size, moving from ß = 0.134, 95% CI = 0.079, 0.188 for EA2, to ß = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent's PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from ß = 0.201, 95% CI = 0.147, 0.256 to ß = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring - therefore acting via the parenting environment - was increased in effect size from ß = 0.058, 95% CI = 0.003, 0.114 to ß = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual's own genetic inheritance and are mediated by parental socioeconomic competence.